title: Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling.
abstract: How prostate cancer is initiated remains a topic of debate. In an effort to establish a human model of prostate carcinogenesis, we adapted premalignant human prostate EPT2-D5 cells to protein-free medium to generate numerous tight prostate spheres (D5HS) in monolayer culture. In contrast to EPT2-D5 cells, the newly generated D5HS efficiently formed large subcutaneous tumors and subsequent metastases in vivo, showing the tumorigenicity of D5HS spheres. A striking production of interleukin (IL)-6 mRNA and protein was found in D5HS cells. The essential roles of IL-6 and the downstream STAT3 signaling in D5HS tumor sphere formation were confirmed by neutralizing antibody, chemical inhibitors, and fluorescent pathway reporter. In addition, elevated reactive oxygen species (ROS) produced upon protein depletion was required for the activation of IL-6/STAT3 in D5HS. Importantly, a positive feedback loop was found between ROS and IL-6 during tumor sphere formation. The association of ROS/IL-6/STAT3 to the carcinogenesis of human prostate cells was further examined in xenograft tumors and verified by limiting dilution implantations. Collectively, we have for the first time established human prostate tumor-initiating cells based on physiologic adaption. The intrinsic association of ROS and IL-6/STAT3 signaling in human prostate carcinogenesis shed new light on this relationship and define therapeutic targets in this setting.
authors.affiliation: Authors' Affiliations: The Gade Institute, Broegelmann Research Laboratory, Department of Clinical Science, Department of Medicine, University of Bergen; Departments of Microbiology and Pathology, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital; KinN Therapeutics AS, Bergen, Norway; College of Pharmacy, Second Military Medical University, Shanghai, PR China; Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Zhejiang-California International NanoSystems Institute, Zhejiang University, Hangzhou, PR China; Swedish Medical Center; and Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qu
authors.forename: Anne Margrete
authors.initials: AM
authors.lastname: Oyan
authors.forename: Runhui
authors.initials: R
authors.lastname: Liu
authors.forename: Yaping
authors.initials: Y
authors.lastname: Hua
authors.forename: Jigang
authors.initials: J
authors.lastname: Zhang
authors.forename: Randi
authors.initials: R
authors.lastname: Hovland
authors.forename: Mihaela
authors.initials: M
authors.lastname: Popa
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Liu
authors.forename: Karl A
authors.initials: KA
authors.lastname: Brokstad
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
authors.forename: Wei-dong
authors.initials: WD
authors.lastname: Zhang
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.forename: Karl-Henning
authors.initials: KH
authors.lastname: Kalland
authors.forename: Xi-Song
authors.initials: XS
authors.lastname: Ke
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D011471:Prostatic Neoplasms / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D015850:Interleukin-6; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human